From Genetic Association To Disease Biology: 2d And 3d Human Ipsc Models of Neuropsychiatric Disorders and Crispr/Cas9 Genome Editing

Abstract

Overall Abstract Recent genome-wide association studies (GWAS) under the framework of the Psychiatric Genomics Consortium (PGC), along with large-scale sequencing efforts, have identified a plethora of disease risk loci with common and/or rare risk variants. Translating these exciting genomic findings into causation and disease biology offers the promise of developing more tailored therapies in psychiatry. Large-scale transcriptomic studies in postmortem brains (e.g., CommonMind Consortium) and in lymphoblastoid cell lines (e.g., the Molecular Genetics of Schizophrenia Consortium) have re-confirmed the polygenic nature of psychiatric disease and provided novel biological insights for some risk loci. However, understanding the disease biology underlying most GWAS findings remains challenging. An important challenge is the paucity of disease-relevant biological materials for assaying molecular and cellular phenotypes associated with risk loci. Human neurons derived from induced pluripotent stem cells (iPSCs), both monolayer cultures (2D model) and the emerging brain organoids or spheroids (3D model), provide a promising alternative to human brains for recapitulating cellular phenotypes of psychiatric disorders. CRISPR/Cas9 editing could further strengthens these models by enabling the generation of isogenic lines with essentially the same genetic background on which allelic effects of a risk variant can be directly compared, thus increasing the sensitivity to detect typically small effects of a GWAS variant. Proof-of-principle studies from NextGen Genetic Association Studies (Cell Stem Cell special issue, April 2017) have demonstrated the promise of molecular profiling and genome editing of iPSC models in identifying causal variants/genes of heart, lung, and blood diseases. Our symposium aims to present similar studies that use iPSC-derived neurons or brain organoids to model molecular/cellular phenotypes, as well as developmental aspects, of psychiatric disorders. Dr. Joachim Hallmayer will first review the current status of using iPSCs for disease modeling, with autism as example to demonstrate how to tackle both monogenic and idiopathic forms of autism. Dr. Jubao Duan will then present the prioritization of putatively functional noncoding schizophrenia risk variants based on open chromatin profiles of iPSC-derived neurons, showing that a common noncoding GWAS risk SNP has detectable biological effects in CRISPR/Cas9-edited isogenic iPSC neurons. The 3rd talk by Dr. Sergiu Pasca, who is an expert in 3D iPSC modeling (Nature, 2017), will present exciting progress on building 3D models of human nervous system to study neurodevelopmental aspects of psychiatric disorders. In the 4th talk, Dr. Joseph Buxbaum will present gene expression profiling in iPSC-derived neurons of case-siblings pairs of rare genetic disorders associated with autism, and provide an approach to address the heterogeneous nature of psychiatric disorders in iPSC disease modeling by scaling up the sample size for transcriptomic profiling via robotic reprogramming and differentiation. Lastly, Dr. Pablo Gejman (discussant) will discuss challenges and limitations of using iPSC models for psychiatric disorders. Together, this symposium will provide novel insights into how iPSC models, empowered by genome-editing technology and/or automation of iPSC reprograming, can bridge gaps in understanding the disease biology and mechanisms underlying the genetic associations.